This application claims priority to U.S. Provisional Patent Application Ser. No. 60/590,190, entitled “4H-4-Oxoquinolizine Derivatives Having Improved Target Selectivity,” filed on Jul. 22, 2004, the entire content of which is hereby incorporated by reference.
This invention relates to compounds of rifamycin origin having antimicrobial activities, their compositions, methods of preparation, and methods for treatment or prevention of infectious disease. More particularly, the rifamycin derivatives of the current invention comprise a rifamycin moiety covalently linked to a linker at the C-3 carbon of the rifamycin moiety and the linker is, in turn, covalently linked to a 4H-4-oxoquinolizine moiety. The invention pertains to the preferred chirality of the linker at its pro-chiral carbon center, which contributes to the antibacterial activities of the compounds. This invention also encompasses chemical processes that address the chirality of the linker and the synthesis of the compounds. The rifamycin derivatives of the present invention are active against drug-resistant microorganisms with reduced frequency of developing mutational resistance.
Rifamycins are natural products with potent antimicrobial activity. Examples of the naturally-occurring rifamycins are rifamycin B, rifamycin O, rifamycin R, rifamycin U, rifamycin S, rifamycin SV and rifamycin Y (Brufani, M., Cerrini, S., Fedeli, W., Vaciago, A. J. Mol. Biol. 1974, 87, 409-435). The therapeutic applications of the naturally-occurring rifamycins are limited due to their poor pharmacokinetics and oral bioavailability, weak activity against Gram-negative pathogens and low distribution into the infected tissues. Chemical modifications result in many semi-synthetic rifamycin derivatives with improved spectrum and pharmacological profiles. Among the semi-synthetic compounds, rifampin, rifabutin and rifapetine have been developed into therapeutic agents and are currently used for the treatment of tuberculosis and other microbial infections (Farr, B. M. Rifamycins, in Principles and Practice of Infectious Diseases; Mandell, G. L., Bennett, J. E., Dolin, R., Eds.; Churchhill Livingstone: Philadelphia; p348-361).
One major liability associated with the current rifamycin class of antimicrobial agents, such as rifampin, however, is their rapid development of microbial resistance. Mutations in their antibacterial target RNA polymerase are mainly responsible for the high frequency of microbial resistance to rifamycins. Thus, there is a need to have new compounds addressing the rifamycin liability. The compounds of the present invention are chemically designed to address drug resistance to both the rifamycin and quinolone class of antibiotics by chemically linking rifamycin and quinolone antibacterial pharmacophores together through a stable bivalent linker. The novel inventive rifamycin compounds exert their antimicrobial activity through multiple antibacterial mechanisms targeting bacterial RNA polymerase, DNA gyrase and DNA topoisomerase IV, and, therefore, they exhibit reduced frequency of resistance, and slow or eliminate development of drug resistance.
Reference is made to PCT application WO 03/045319 A2 that discloses rifamycin derivatives formed by linking rifamycin and a therapeutic drug and the use of them as vehicles for delivering the therapeutic drug.
However, this reference does not describe any drug that is introduced to the C-3 position of a rifamycin molecule. The reference also fails to demonstrate by example that a quinolone antibiotic or its pharmacophore structure is linked to any position of rifamycin molecule.